Desmoid-type fibromatosis of the mesentery: a clinicopatho-logical and genetic analysis of 9 cases. / è‚ ç³»è†œéŸ§å¸¦æ ·çº¤ç»´ç˜¤ç— æ‚£è€ ä¸´åºŠç— ç†å­¦åˆ†æž.

Nine cases of mesenteric desmoid-type fibromatosis were diagnosed and treated in Taizhou Hospital, Wenzhou Medical University between January 2010 and May 2022, including 2 females and 7 males, aged 16 to 59 years. The lesions were in the mesentery of small intestine with 7 cases, ileocecal junction with 1 cases and transverse colon with 1 case. The tumors had an unclear boundary and no envelope, the section was solid, gray and tough. The mean maximum diameter was (10.7±8.5) cm (range 3.5-33.0 cm). Microscopically, fusiform fibroblasts and myofibroblasts were parallel, bunched or staggered, buried in a large amount of extracellular collagen. The cell morphology was relatively consistent, without obvious atypia, and mitosis was rare. Immunohistochemistry showed that the tumor cells were positive for vimentin (9/9), ß-catenin (9/9), while smooth muscle actin (5/9) stains were focally positive. Ki-67 proliferation index was 1%-10%. Cytokeratin Pan, S-100, STAT6, CD117, DOG1, CD34, desmin and anaplastic lymphoma kinase stains were negative. Genetic analysis showed that there were 7 cases of c.121G>A(p.Thr41Ala) mutation of CTNNB1 gene, 1 case of c.121G>A(p.Thr41Ala) and 1 case of c.134C>T(p.Ser45Phe) double mutation, and 1 case of wild type. Tumors were surgically resected in all 9 cases. Eight cases had no recurrence or metastasis, 1 case had recurrence 6 months later, and no recurrence or metastasis after additional surgical resection.

A Rare Cause of Abdominal Pain: IgG4-Related Sclerosing Mesenteritis.

A 67-year-old man with previous cardiovascular disease was referred to our consultation due to a 5-month history of recurrent epigastric pain. Esophagogastroduodenoscopy and full blood workup presented no alterations. CT scan showed an irregularly shaped mass at the root of the mesentery, measuring 40x25x47mm, with spiculated contours and retractile behaviour (a). Simultaneous densification of the adjacent fat and infracentimetric ganglionic formations scattered throughout the mesentery were shown. Surgical biopsy revealed extensive storiform fibrosclerosis, with the presence of interstitial lymphoplasmocytic infiltrate and obliterative phlebitis (b); the plasma cells had mostly IgG expression, with IgG4:IgG ratio >40% (c), accounting for more than 30- 40 IgG4 plasma cells per field. The serum IgG4 level was 137mg/dL. A diagnosis of IgG4-related sclerosing mesenteritis was made, without other organ involvement. Prednisolone (0.6mg/kg/d) improved partially the abdominal pain, so steroid sparing strategy with off-label rituximab was associated. Due to its low prevalence, the understanding of this entity is scarce, and its diagnosis is challenging. Unlike other manifestations of IgG4-related disease, the intra-abdominal disease is identified in later stages, due to unspecific symptoms. This case aims to raise awareness about this condition as a differential diagnosis of abdominal pain.

Creeping fat formation and interaction with intestinal disease in Crohn's disease.

Creeping fat (CrF), also known as fat wrapping, is a significant disease characteristic of Crohn's disease (CD). The transmural inflammation impairs intestinal integrity and facilitates bacteria translocation, aggravating immune response. CrF is a rich source of pro-inflammatory and pro-fibrotic cytokines with complex immune microenvironment. The inflamed and stricturing intestine is often wrapped by CrF, and CrF is associated with greater severity of CD. The large amount of innate and adaptive immune cells as well as adipocytes in CrF promote fibrosis in the affected intestine by secreting large amount of pro-fibrotic cytokines, adipokines, growth factors and fatty acids. CrF is a potential therapeutic target for CD treatment and a promising bio-marker for predicting response to drug therapy. This review aims to summarize and update the clinical manifestation and application of CrF and the underlying molecular mechanism involved in the pathogenesis of intestinal inflammation and fibrosis in CD.

Effect of Crohn's disease mesenteric mesenchymal stem cells and their extracellular vesicles on T-cell immunosuppressive capacity.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal intestinal tract and has characteristic hypertrophic adipose changes observed in the mesentery. To better understand the role of the mesentery in the pathophysiology of Crohn's disease (CD), we evaluated the immunomodulatory potential of mesenchymal stem cells (MSCs) and their secreted extracellular vesicles (EVs) derived from Crohn's patients. MSCs and EVs were isolated from the mesentery and subcutaneous tissues of CD patients and healthy individuals subcutaneous tissues, and were analysed for differentiation, cytokine expression, self-renewal and proliferation. The varying capacity of these tissue-derived MSCs and EVs to attenuate T-cell activation was measured in in vitro and an in vivo murine model. RNA sequencing of inflamed Crohn's disease mesentery tissue revealed an enrichment of T-cell activation compared to non-inflamed subcutaneous tissue. MSCs and MSC-derived EVs isolated from Crohn's mesentery lose their ability to attenuate DSS-induced colitis compared to subcutaneous tissue-derived cell or EV therapy. We found that treatment with subcutaneous isolated MSCs and their EV product compared to Crohn's mesentery MSCs or EVs, the inhibition of T-cell proliferation and IFN-γ, IL-17a production increased, suggesting a non-inflamed microenvironment allows for T-cell inhibition by MSCs/EVs. Our results demonstrate that Crohn's patient-derived diseased mesentery tissue MSCs lose their immunosuppressive capacity in the treatment of colitis by distinct regulation of pathogenic T-cell responses and/or T-cell infiltration into the colon.

Age-Associated B Cell Features of the Murine High-Grade B Cell Lymphoma Bc.DLFL1 and Its Extranodal Expansion in Abdominal Adipose Tissues.

Diffuse large B cell lymphoma comprises a heterogeneous group of B cell-derived tumors, with different degrees of aggressiveness, as defined by their cellular origin and tissue microenvironment. Using the spontaneous Bc.DLFL1 lymphoma originating from a BALB/c mouse as a diffuse large B cell lymphoma model, in this study we demonstrate that the lymphoma cells display surface phenotype, IgH V-region somatic mutations, transcription factor characteristics and in vivo location to splenic extrafollicular regions of age-associated B cells (ABCs), corresponding to T-bet+ and Blimp-1+/CD138- plasmablasts derivation. The expansion of lymphoma cells within lymphoid tissues took place in a close arrangement with CD11c+ dendritic cells, whereas the extranodal infiltration occurred selectively in the mesentery and omentum containing resident gp38/podoplanin+ fibroblastic reticular cells. Antagonizing BAFF-R activity by mBR3-Fc soluble receptor fusion protein led to a significant delay of disease progression. The extranodal expansion of Bc.DLFL1 lymphoma within the omental and mesenteric adipose tissues was coupled with a significant change of the tissue cytokine landscape, including both shared alterations and tissue-specific variations. Our findings indicate that while Bc.DLFL1 cells of ABC origin retain the positioning pattern within lymphoid tissues of their physiological counterpart, they also expand in non-lymphoid tissues in a BAFF-dependent manner, where they may alter the adipose tissue microenvironment to support their extranodal growth.

Pygopus2 ameliorates mesenteric adipocyte poor differentiation to alleviate Crohn's disease -like colitis via the Axin2/GSK3ß pathway.

OBJECTIVES: Crohn's disease (CD) mesenteric adipose tissue (MAT) inflammation affects enteritis through the interaction between the mesentery and intestine, and we previously found that poorly differentiated mesenteric adipocytes were related to its inflammatory features. Pygopus2 (Pygo2) is a key negative regulator of adipocyte differentiation. We aimed to determine whether Pygo2 participates in CD mesenteric lesions and whether Pygo2 knockdown would be beneficial in a CD model (Il-10-/- mice). METHODS: Pygo2 expression in MAT from control and CD patients and Il-10-/- mice was measured by immunohistochemistry. Lentiviral transfection was used to regulate Pygo2 expression in Il-10-/- mice, and the effects on mesenteric adipocyte differentiation, inflammation, and dysfunction during spontaneous colitis, as well as the possible mechanism, were investigated. RESULTS: Pygo2 expression was increased in MAT from CD patients and Il-10-/- mice, and its expression correlated with poor adipocyte differentiation and inflammation. Pygo2 knockdown significantly ameliorated colitis in Il-10-/- mice. Moreover, the downregulation of Pygo2 gene expression could promote adipocyte differentiation and inhibit adipocyte inflammation in vivo and in vitro, and the effects were at least partly mediated by the Axis inhibition protein 2 (Axin2)/glycogen synthase kinase 3 beta (GSK3ß) pathway. CONCLUSIONS: The increase in Pygo2 may be related to mesenteric adipocyte poor differentiation and inflammatory features of CD, and Pygo2 inhibition could alleviate CD-like colitis by improving mesenteric lesions by regulating the Axin2/GSK3ß pathway.

Whole blood resuscitation restores intestinal perfusion and influences gut microbiome diversity.

OBJECTIVE: Gut dysbiosis, an imbalance in the gut microbiome, occurs after trauma, which may be ameliorated with transfusion. We hypothesized that gut hypoperfusion following trauma causes dysbiosis and that whole blood (WB) resuscitation mitigates these effects. METHODS: Anesthetized rats underwent sham (S; laparotomy only, n = 6); multiple injuries (T; laparotomy, liver and skeletal muscle crush injuries, and femur fracture, n = 5); multiple injuries and 40% hemorrhage (H; n = 7); and multiple injuries, hemorrhage, and WB resuscitation (R; n = 7), which was given as 20% estimated blood volume from donor rats 1 hour posttrauma. Baseline cecal mesenteric tissue oxygen (O2) concentration was measured following laparotomy and at 1 hour and 2 hours posttrauma. Fecal samples were collected preinjury and at euthanasia (2 hours). 16S rRNA sequencing was performed on purified DNA, and diversity and phylogeny were analyzed with QIIME (Knight Lab, La Jolla, CA; Caporaso Lab, Flagstaff, AZ) using the Greengenes 16S rRNA database (operational taxonomic units; 97% similarity). α and ß diversities were estimated using observed species metrics. Permutational analysis of variance was performed for overall significance. RESULTS: In H rats, an average decline of 36% ± 3.6% was seen in the mesenteric O2 concentration at 1 hour without improvement by 2 hours postinjury, which was reversed following resuscitation at 2 hours postinjury (4.1% ± 3.1% difference from baseline). There was no change in tissue O2 concentration in the S or T rats. ß Diversity differed among groups for all measured indices except Bray-Curtis, with the spatial median of the S and R rats more similar compared with S and H rats (p < 0.05). While there was no difference in α diversity found among the groups, indices were significantly correlated with mesenteric O2 concentration. Members of the family Enterobacteriaceae were significantly enriched in only 2 hours. CONCLUSION: Mesenteric perfusion after trauma and hemorrhage is restored with WB resuscitation, which influences ß diversity of the gut microbiome. Whole blood resuscitation may also mitigate the effects of hemorrhage on intestinal dysbiosis, thereby influencing outcomes.

Analysis of Lymphatic Vessel Formation by Whole-Mount Immunofluorescence Staining.

Pathological alterations of lymphatic structure and function interfere with lymph transport, resulting in a wide range of clinical disorders that include edema, tissue inflammation, and metabolic syndromes. Mesentery contains abundant lymphatic vessels and plays an important role in transporting absorbed lipid from the intestine. In this manuscript, we describe a whole-mount staining method on isolated mouse mesentery with VEGFR3, Prox1, and Lyve1 antibodies to visualize the morphology of lymphatic vessels.

Increased proinflammatory cytokines in mesenteric fat in major surgery and Crohn's disease.

BACKGROUND: Proinflammatory cytokines play an important role in abdominal surgery and are often associated with the development of postoperative ileus, especially in Crohn's disease. The aim of this study was to investigate proinflammatory cytokine levels in mesenteric fat in Crohn's disease and patients without Crohn's disease. METHODS: Human mesenteric tissue specimen were divided into 3 patient groups (n = 10 each): minor surgery (laparoscopic cholecystectomy), major surgery (colectomy) in patients without Crohn's disease, and major surgery (colectomy) in patients with Crohn's disease. Levels of interleukin 6, interleukin 1-ß, and tumor necrosis factor α were determined by cytometric bead array, enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. The Kruskal-Wallis and the Mann-Whitney U test were used to compare continuous variables. For categorical variables, the χ2 test or Fisher exact test was used. RESULTS: In minor surgery, cytokines levels of interleukin 6, interleukin 1-ß and Tumor necrosis factor α were low (ie, interleukin 6: 1 pg/mL [0-36], interleukin 1-ß: 0 fg/mL [0-18], tumor necrosis factor α: 157 fg/mL [91-237]) compared with major surgery in patients with and without Crohn's disease. Cytokines were significantly higher in major surgery (ie, interleukin 6: 147 pg/mL [29-347], interleukin 1-ß: 660 fg/mL [0-2580], tumor necrosis factor α: 532 fg/mL [289-1647]; P = .02 and major surgery with CD (cytometric bead array: interleukin 6: 94 pg/mL [24-627], interleukin 1-ß: 708 fg/mL [0-1664], tumor necrosis factor α: 733 fg/mL [209-1,354]; P < .05). Cytokine levels in major surgery with Crohn's disease showed a further increase of interleukin 6 in polymerase chain reaction in comparison to major surgery in patients without Crohn's disease (1.2 vs 4, P = .04). CONCLUSION: Proinflammatory cytokines are increased in the mesenteric fat in major operations compared to minor operations, which indicates local mesenteric inflammation. In Crohn's disease, levels of proinflammatory cytokines are even higher, which may put the patients at risk for postoperative ileus.

The role of mesenteric lymph exosomal lipid mediators following intestinal ischemia-reperfusion injury on activation of inflammation.

BACKGROUND: Intestinal ischemia caused by hemorrhagic shock is known to induce systemic inflammatory responses. Previous studies have shown that mesenteric lymph (ML) plays a crucial role in gut-mediated inflammation. Lipid mediators, such as lysophosphatidylcholines (LPCs), which contain polyunsaturated fatty acids (PUFAs), are present in the postshock ML. Exosomes are also present in the ML and act as transcellular carriers of lipids; however, their role in postshock systemic inflammation has not been revealed. Here, we aimed to identify changes in lipid mediators in ML exosomes after intestinal ischemia. METHODS: Male Sprague-Dawley rats underwent laparotomy, followed by ML duct cannulation. Animals were subjected to 60 minutes of intestinal ischemia by superior mesenteric artery clamping, followed by 120 minutes of reperfusion. Mesenteric lymph was obtained before and after intestinal ischemia, and exosomes were isolated from ML by ultracentrifugation. The biological activity of ML exosomes was determined using the monocyte nuclear factor κB (NF-κB) activation assay. Lipids of ML exosomes were extracted and quantified by liquid chromatography/electrospray ionization mass spectrometry. RESULTS: Mesenteric lymph exosome-induced NF-κB activation significantly increased after intestinal ischemia, and lipid analysis revealed a significant increase in the concentration of PUFA-containing LPCs. In addition, PUFA-containing LPCs also induced NF-κB activation. CONCLUSION: Our results suggest that biologically active lipid mediators in ML exosomes may be involved in the inflammatory response after intestinal ischemia.

Alkaline Phosphatase Activity Is a Key Determinant of Vascular Responsiveness to Norepinephrine.

Here, we tested the hypothesis that TNAP (tissue nonspecific alkaline phosphatase) modulates vascular responsiveness to norepinephrine. In the isolated, Tyrode's-perfused rat mesentery, 50 µmol/L of L-p-bromotetramisole (L-p-BT; selective TNAP inhibitor, Ki=56 µmol/L) significantly reduced TNAP activity and caused a significant 9.0-fold rightward-shift in the norepinephrine concentration versus vasoconstriction relationship. At 100 µmol/L, L-p-BT further reduced mesenteric TNAP activity and caused an additional significant right-shift of the norepinephrine concentration versus vasoconstriction relationship. A higher concentration (200 µmol/L) of L-p-BT had no further effect on either mesenteric TNAP activity or norepinephrine-induced vasoconstriction. L-p-BT did not alter vascular responses to vasopressin, thus ruling-out nonspecific suppression of vascular reactivity. Since in the rat mesenteric vasculature α1-adrenoceptors mediate norepinephrine-induced vasoconstriction, these finding indicate that TNAP inhibition selectively interferes with α1-adrenoceptor signaling. Additional experiments showed that the effects of TNAP inhibition on norepinephrine-induced vasoconstriction were not mediated by accumulation of pyrophosphate or ATP (TNAP substrates) nor by reduced adenosine levels (TNAP product). TNAP inhibition significantly reduced the Hillslope of the norepinephrine concentration versus vasoconstriction relationship from 1.8±0.2 (consistent with positive cooperativity of α1-adrenoceptor signaling) to 1.0±0.1 (no cooperativity). Selective activation of A1-adenosine receptors, which are known to participate in coincident signaling with α1-adrenoceptors, reversed the suppressive effects of L-p-BT on norepinephrine-induced vasoconstriction. In vivo, L-p-BT administration achieved plasma levels of ≈60 µmol/L and inhibited mesenteric vascular responses to exogenous norepinephrine and sympathetic nerve stimulation. TNAP modulates vascular responses to norepinephrine likely by affecting positive cooperativity of α1-adrenoceptor signaling via a mechanism involving A1 receptor signaling.

Dietary polyacetylene falcarinol upregulated intestinal heme oxygenase-1 and modified plasma cytokine profile in late phase lipopolysaccharide-induced acute inflammation in CB57BL/6 mice.

Unlike polyphenols, which are widely available in the diet, polyacetylenes are available only from the Apiaceae family vegetables, including carrot, parsnip, fennel, celery, and many herbs (parsley, lovage, etc). The aim of this study was to investigate the hypothesis that polyacetylene falcarinol (FA) reduces intestinal inflammation and examine its similarity of effect to isothiocyanate R-sulforaphane during the late phase of acute inflammation. To this end, 3-month-old male CB57BL/6 mice were fed twice daily for 1 week with 5 mg/kg of FA, sulforaphane, or vehicle before receiving an intraperitoneal injection of 5 mg/kg endotoxin (lipopolysaccharide [LPS]) to induce modest acute inflammation. The expression of intestinal and hepatic heme oxygenase-1 at the mRNA and protein levels, circulating cytokines, as well as intestinal and mesenteric n-6 and n-3 fatty acid lipid mediators was compared 24 hours after LPS administration to examine its effects on the late phase of inflammation. Intestinal nuclear factor (erythroid-derived 2)-like 2 target enzyme heme oxygenase-1 was upregulated 8.42-fold at the mRNA level and 10.7-fold at the protein level by FA-supplemented diet. However, the FA-supplemented diet produced a unique type-2 plasma cytokine skew after LPS treatment. Plasma cytokines interleukin (IL)-4, IL-13, IL-9, and IL-10 were upregulated, reflecting the cytokine profile of reduced type 1 inflammation. A detailed lipidomic analysis of n-6 and n-3 fatty acid pro- and anti-inflammatory pathways in the mesentery and intestinal mucosa showed that FA diet was more similar to the control groups than to other LPS treated groups. In this study, we demonstrated that FA-supplemented diet produced a unique immunomodulatory effect not observed with sulforaphane in late phases of inflammation. These results support the hypothesis that FA may have role as a dietary immunosuppressant in patients with inflammatory gastrointestinal as well as other inflammatory disorders that may be alleviated by increasing consumption of carrot or other FA-containing food sources.

Mesentery - a 'New' organ.

The mesentery is the organ in which all abdominal digestive organs develop, and which maintains these in systemic continuity in adulthood. Interest in the mesentery was rekindled by advancements of Heald and Hohenberger in colorectal surgery. Conventional descriptions hold there are multiple mesenteries centrally connected to the posterior midline. Recent advances first demonstrated that, distal to the duodenojejunal flexure, the mesentery is a continuous collection of tissues. This observation explained how the small and large intestines are centrally connected, and the anatomy of the associated peritoneal landscape. In turn it prompted recategorisation of the mesentery as an organ. Subsequent work demonstrated the mesentery remains continuous throughout development, and that abdominal digestive organs (i.e. liver, spleen, intestine and pancreas) develop either on, or in it. This relationship is retained into adulthood when abdominal digestive organs are directly connected to the mesentery (i.e. they are 'mesenteric' in embryological origin and anatomical position). Recognition of mesenteric continuity identified the mesenteric model of abdominal anatomy according to which all abdominal abdomino-pelvic organs are organised into either a mesenteric or a non-mesenteric domain. This model explains the positional anatomy of all abdominal digestive organs, and associated vasculature. Moreover, it explains the peritoneal landscape and enables differentiation of peritoneum from the mesentery. Increased scientific focus on the mesentery has identified multiple vital or specialised functions. These vary across time and in anatomical location. The following review demonstrates how recent advances related to the mesentery are re-orientating the study of human biology in general and, by extension, clinical practice.

TIM-3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis.

This report offers novel clinical and diagnostic aspects of the association between germline mutations in HAVCR2 and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The patient presented with panniculitis-like T-cell lymphoma involving mesenteric fatty tissue associated with hemophagocytic lymphohistiocytosis (HLH). Five years later, he developed a clonally unrelated SPTCL and underwent hematopoietic stem cell transplantation. Retrospectively, he was found to carry germline mutations in HAVCR2 associated with reduced T-cell immunoglobulin mucin-3 (TIM-3) expression. We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool.

Dendritic Cells of Mesenteric and Regional Lymph Nodes Contribute to Yersinia enterocolitica O:3-Induced Reactive Arthritis in TNFRp55-/- Mice.

Dendritic cells (DCs) participate in the pathogenesis of several diseases. We investigated DCs and the connection between mucosa and joints in a murine model of Yersinia enterocolitica O:3-induced reactive arthritis (ReA) in TNFRp55-/- mice. DCs of mesenteric lymph nodes (MLN) and joint regional lymph nodes (RLN) were analyzed in TNFRp55-/- and wild-type mice. On day 14 after Y. enterocolitica infection (arthritis onset), we found that under TNFRp55 deficiency, migratory (MHChighCD11c+) DCs increased significantly in RLN. Within these RLN, resident (MHCintCD11c+) DCs increased on days 14 and 21. Similar changes in both migratory and resident DCs were also detected on day 14 in MLN of TNFRp55-/- mice. In vitro, LPS-stimulated migratory TNFRp55-/- DCs of MLN increased IL-12/23p40 compared with wild-type mice. In addition, TNFRp55-/- bone marrow-derived DCs in a TNFRp55-/- MLN microenvironment exhibited higher expression of CCR7 after Y. enterocolitica infection. The major intestinal DC subsets (CD103+CD11b-, CD103-CD11b+, and CD103+CD11b+) were found in the RLN of Y. enterocolitica-infected TNFRp55-/- mice. Fingolimod (FTY720) treatment of Y. enterocolitica-infected mice reduced the CD11b- subset of migratory DCs in RLN of TNFRp55-/- mice and significantly suppressed the severity of ReA in these mice. This result was associated with decreased articular IL-12/23p40 and IFN-γ levels. In vitro FTY720 treatment downregulated CCR7 on Y. enterocolitica-infected bone marrow-derived DCs and purified MLN DCs, which may explain the mechanism underlying the impairment of DCs in RLN induced by FTY720. Taken together, data indicate the migration of intestinal DCs to RLN and the contribution of these cells in the immunopathogenesis of ReA, which may provide evidence for controlling this disease.

Recurrent and metastatic extragastrointestinal stromal tumors of the mesentery with C-KIT and PDGFRA mutations: a case report.

EGISTs originating outside the gastrointestinal tract share some similarities with the GISTs regarding their immunohistochemical features including the positive expression of CD117 and CD34. The majority of EGISTs carry activating mutations of the C-KIT or PDGFRA genes. However, there is no precedent in the literature where the two mutations occur in one case of EGISTs to date. We describe herein, a 52-year-old female who presented as mesenteric and pelvic regions masses showing positive immunoreactivity for CD117, DOG-1, CD34. Mutation analysis identified two mutations that located in the exon 13 of C-KIT and in the exon 18 of PDGFRA. The patient was treated sequentially with imatinib, sunitinib, sorafenib, and regorafenib. However, the prognosis was undesirable. Previous research has shown that expression of members of Bcl-2 family may be helpful in predicting prognosis, the survival time, and the resistance to chemotherapeutic agents. IHC was performed to detect the expression of BCL-2 family. The results show that high BCL-2 expression and low BAX expression in both specimens. In conclusion, our case may suggest that the presence of both C-KIT and PDGFRA mutations in EGISTs patients may indicate a very poor prognosis; and the expression level of BCL-2 and BAX could predict clinical outcome.

Foliate Lymphoid Aggregates as Novel Forms of Serous Lymphocyte Entry Sites of Peritoneal B Cells and High-Grade B Cell Lymphomas.

The cellular homeostasis of lymphoid tissues is determined by the continuous interactions of mobile hematopoietic cells within specialized microenvironments created by sessile stromal cells. In contrast to the lymph nodes and mucosal lymphoid tissues with well-defined entry and exit routes, the movement of leukocytes in the peritoneal cavity is largely unknown. In this study, we report that, in addition to the omental milky spots and fat-associated lymphoid clusters, in mice, the serous surface of the mesenteric adipose streaks contains lymphocyte-rich organoids comprised of a highly compacted leaf-like part connected to the adipose tissue that can also efficiently bind B cells and high-grade B cell lymphoma (diffuse large B cell lymphoma) cells. Denoted as foliate lymphoid aggregates (FLAgs), these structures show incomplete T/B segregation and a partially differentiated stromal architecture. LYVE-1-positive macrophages covering FLAgs efficiently bind i.p. injected normal B cells as well as different types of diffuse large B cell lymphoma cells. Within FLAgs, the lymphocytes compartmentalize according to their chemokine receptor pattern and subsequently migrate toward the mesenteric lymph nodes via the mesenteric lymphatic capillaries. The blood supply of FLAgs includes short vascular segments displaying peripheral lymph node addressin, and the extravasation of lymphocytes to the omental and mesenteric adipose tissues is partly mediated by L-selectin. The appearance of i.p. injected cells in mesenteric lymph nodes suggests that the mesentery-associated lymphatics may also collect leukocytes from the fat-associated lymphoid clusters and FLAgs, thus combining the mucosal and serous exit of mobile leukocytes and increasing the range of drainage sites for the peritoneal expansion of lymphoid malignancies.

Effects of zearalenone-induced oxidative stress and Keap1-Nrf2 signaling pathway-related gene expression in the ileum and mesenteric lymph nodes of post-weaning gilts.

Zearalenone (ZEA) contamination of feed affects animal husbandry and the human health. Currently, the molecular mechanism underlying small intestine-related diseases caused by ZEA-induced oxidative stress is not well understood. In this study, we aimed to identify the mechanisms involved in ZEA (0.5-1.5 mg/kg)-induced oxidative stress in the ileum and mesenteric lymph nodes (MLNs) and the role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in post-weaning gilts. Forty post-weaning gilts (Landrace × Yorkshire × Duroc) with an average body weight of 14.01 ± 0.86 kg were randomly allocated to four groups and fed a corn-soybean meal basal diet supplemented with < 0.1, 0.5, 1.0, or 1.5 mg/kg ZEA. The results showed that the activity of total superoxide dismutase and glutathione peroxidase decreased (p < 0.05) linearly and quadratically and that the content of malondialdehyde increased (p < 0.05) quadratically in the ileum and MLNs with increasing ZEA in the diet. Immunohistochemical analysis showed that the expression of Nrf2 and glutathione peroxidase 1 (Gpx1) immunoreactive proteins in the ileum and MLNs were significantly enhanced with increasing ZEA. The relative mRNA and protein expression of Nrf2, Gpx1, quinone oxidoreductase 1 (Nqo1), hemeoxygenase 1 (Ho1), modifier subunit of glutamate-cysteine ligase (Gclm), and catalytic subunit of glutamate-cysteine ligase (Gclc) increased (p < 0.05) linearly and quadratically, and the relative mRNA and protein expression of Keap1 decreased (p < 0.05) linearly and quadratically in the ileum with increasing ZEA concentrations in the diet. Further, the relative mRNA and protein expression of Nrf2 and Gpx1 increased (p < 0.05) linearly and quadratically, and the relative mRNA and protein expression of Nqo1, Ho1, and Gclm decreased (p < 0.05) quadratically in the MLNs as ZEA concentrations increased in the diet. Our results provide valuable genetic information on ZEA-induced oxidative stress in the ileum and MLNs of post-weaning gilts and have elucidated the key regulatory genes involved in the Keap1-Nrf2 signaling pathway. Results indicated that the Keap1-Nrf2 signaling pathway might be a key target to further prevent and treat ZEA-induced injury to the ileum in post-weaning gilts.

Mesenteric Adipose Tissue Alterations in Crohn's Disease Are Associated With the Lymphatic System.

Background: Mesenteric fat wrapping and thickening are typical characteristics of Crohn's disease (CD). The purpose of this study was to explore the cause of mesenteric adipose hypertrophy and analyze the role of lymphatic vessels in mesenteric adipose tissue in CD. Methods: Twenty-three CD patients who underwent ileocolonic resection were included. In CD patients, specimens were obtained from hypertrophic mesenteric adipose tissue (htMAT) next to the diseased ileum. The mesenteric lymphatic vessels in mesenteric adipose tissue were separated under stereoscope microscope. Transmission electron microscopy and immunofluorescence were used to observe the structure of mesenteric lymphatic vessels. The NF-κB signaling pathway in mesenteric adipose tissue was detected in CD specimens using Western blotting. Results: Electron microscopy showed that the structure of mesenteric lymphatic vessel was discontinuous, and the microstructure of lymphatic endothelial cells appeared ruptured and incomplete. Through an immunofluorescence technique, we found that the surface of lymphatic endothelial cells lacked tight junction protein staining in CD. Also, the expression of claudin-1, occludin, and ZO-1 in the mesenteric lymphatic vessel of htMAT was significantly lower than that of control. These results indicated that the structure of the mesenteric lymphatic vessel in htMAT was mispatterned and ruptured, which could lead to lymph leakage. Leaky lymph factors could stimulate adipose tissue to proliferate. Antigens that leaked into the mesenteric adipose tissue could effectively elicit an immune response. The levels of cytokines (TNF-a, IL-1ß, IL-6) was increased in the htMAT of CD patients by activated NF-κB signaling pathway. Conclusions: Our findings demonstrated that the hypertrophy of mesenteric adipose tissue may result from mispatterned and ruptured lymphatic vessels. Alteration of mesenteric adipose tissue was associated with activated NF-κB signaling pathway. This study enhances support for elucidating the importance of mesenteric lymphatic vessels and adipose tissue in CD.

Precious cargo: Modulation of the mesenteric lymph exosome payload after hemorrhagic shock.

BACKGROUND: Trauma/hemorrhagic shock (T/HS) causes a release of proinflammatory mediators into the mesenteric lymph (ML) that may trigger a systemic inflammatory response and subsequent organ failure. Recently, we showed that exosomes in postshock ML are biologically active mediators of this inflammation. Because the specific inflammatory mediators in postshock ML exosomes have yet to be characterized, we hypothesized that T/HS would lead to a distinct ML proinflammatory exosome phenotype that could be identified by proteomic analysis. We further hypothesized that their regulation by the neuroenteric axis via the vagus nerve would modify this proinflammatory profile. METHODS: Male rats underwent an established T/HS model including 60 minutes of HS followed by resuscitation. Mesenteric lymph was collected before HS (preshock) and after resuscitation (postshock). A subset of animals underwent cervical vagus nerve electrical stimulation (VNS) after the HS phase. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) followed by protein identification, label free quantification, and bioinformatic analysis was performed on exosomes from the pre-shock and post-shock phases in the T/HS and T/HS + vagus nerve electrical stimulation groups. Biological activity of exosomes was evaluated using a monocyte nuclear factor kappa B (NF-κB) activity assay. RESULTS: ML exosomes express a distinct protein profile after T/HS with enrichment in pathways associated with cell signaling, cell death and survival, and the inflammatory response. Stimulation of the vagus nerve following injury attenuated the transition of ML exosomes to this T/HS-induced inflammatory phenotype with protein expression remaining similar to pre-shock. Monocyte NF-κB activity was increased after exposure to ML exosomes harvested after T/HS, while ML exosomes from preshock had no effect on monocyte NF-κB expression. CONCLUSION: Postshock ML exosomes carry a distinct, proinflammatory protein cargo. Stimulating the vagus nerve prevents the T/HS-induced changes in ML exosome protein payload and suggests a novel mechanism by which the neuroenteric axis may limit the systemic inflammatory response after injury.